Neutrophils Promote Amphiregulin Production in Intestinal Epithelial Cells through TGF-β and Contribute to Intestinal Homeostasis

Abstract

Neutrophils are the first responders to sites of inflammation when the intestinal epithelial barrier is breached and the gut microbiota invade. Despite current efforts in understanding the role of neutrophils in intestinal homeostasis, the complex interactions between neutrophils and intestinal epithelial cells (IECs) is still not well characterized. In this study, we demonstrated that neutrophils enhanced production of amphiregulin (AREG), a member of the EGFR ligand family, by IECs, which promoted IEC barrier function and tissue repair. Depletion of neutrophils resulted in more severe colitis in mice because of decreased AREG production by IECs upon dextran sodium sulfate (DSS) insult. Administration of AREG restored epithelial barrier function and ameliorated colitis. Furthermore, neutrophil-derived TGF-β promoted AREG production by IECs. Mechanistically, TGF-β activated MEK1/2 signaling, and inhibition of MEK1/2 abrogated TGF-β-induced AREG production by IECs. Collectively, these findings reveal that neutrophils play an important role in the maintenance of IEC barrier function and homeostasis.

Innate immune cell–epithelial crosstalk during wound repair

“…In addition to eliminating microbes and modulating the wound microenvironment through oxygen metabolism, neutrophils release pro-repair cytokines, chemokines, and growth factors that signal through wound-associated immune and epithelial cells to promote healing. Following mucosal damage, infiltrating neutrophils secrete TGF-β to activate MEK1/2 signaling and induce intestinal epithelial cell-mediated production of the EGF-like molecule amphiregulin (AREG) (56). AREG promotes intestinal epithelial cell differentiation and proliferation in a positive manner to facilitate efficient return to mucosal homeostasis in vivo (56,57).…”

“…Following mucosal damage, infiltrating neutrophils secrete TGF-β to activate MEK1/2 signaling and induce intestinal epithelial cell-mediated production of the EGF-like molecule amphiregulin (AREG) (56). AREG promotes intestinal epithelial cell differentiation and proliferation in a positive manner to facilitate efficient return to mucosal homeostasis in vivo (56,57). TGF-β also accelerates re-epithelization, angiogenesis, and granulation tissue formation in healing murine and human skin wounds (58)(59)(60).…”

The Role of Immune Cells and Cytokines in Intestinal Wound Healing

“…In addition to eliminating bacteria and adjusting the wound microenvironment through oxygen metabolism, neutrophils promote wound repair by secreting pro-repair cytokines, chemokines, and growth factors. After dextran sodium sulfate (DSS)-induced mucosal injury, neutrophil-derived transforming growth factor-beta (TGF-β) activates MEK1/2 signaling and induces the production of the EGF-like molecule amphiregulin (AREG) in intestinal epithelial cells, which protects intestinal epithelial barrier function and ameliorates DSS-induced colitis [23].…”

Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

“…AhR signaling can also drive immune responses in favor of either regulatory T cell or Th17 differentiation, suggesting ligand-and cell type-specific effects that could either ameliorate or worsen aGVHD (37,38). AREG is similarly protective in models of colitis and associated with Treg-and T9-mediated tissue repair (39)(40)(41)(42)(43). AREG protein expression in the GI tract during clinical aGVHD can be variable, and the prognosis is largely driven by whether AREG is found in the circulation (unfavorable) or not (favorable) (44,45).…”